Project Summary The Baylor College of Medicine (BCM) Undiagnosed Diseases Network (UDN) Clinical Site (CS) has successfully advanced the objectives of phase I UDN. We established a high throughput integrated pipeline for patients with undiagnosed diseases (UDD) to access a state of the art diagnostic, clinical, and molecular evaluation. We led extramural UDN clinical sites in number of patient acceptances and in person evaluations, while being one of two extramural sites to achieve 100% for these two key milestones. We developed innovative approaches including trio RNA sequencing that led us to achieve a diagnostic rate for solved and strong candidate genes in 45% of cases completed to date. Finally, we engaged the UDN and the broader scientific/lay community in sharing best practices, collaborative discovery, and education. This was achieved by leveraging the integrated genetic and genomic program that is the Department of Molecular and Human Genetics (DMHG) at BCM. The Department is a combination of basic science, clinical, and molecular pathology departments. Because these are consumed under one organizational unit, we have rapidly translated discovery to practice, and served as a nexus for the research community at BCM, the Texas Medical Center, and nationally. The leadership of the DMHG in genetic and genomic medicine at BCM has ensured the integration of the partnering Departments of Pediatrics, Internal Medicine, and Neurology into phase I of the BCM UDN CS. In phase II we propose to apply this integrated approach to achieve the new and ongoing objectives of the UDN. The BCM UDN CS leadership includes established clinical investigators in Genetics, Pediatrics, Medicine, and Neurology who will lead a primary team while drawing from consultants in partner Departments institution-wide. Clinical delineation and subsequent DNA molecular diagnosis will leverage both established (Human Genome Sequencing Center, Baylor Genetics laboratory, and NIH Center for Mendelian Genomics) and BCM UDN CS-specific bioinformatics pipelines. The interpretation and ultimate functional study of genomic data will flow to specialized organ-based research centers including the Center for Skeletal Medicine and Biology (led by Dr. Brendan Lee), the Neurological Research Institute (led by Dr. Huda Zoghbi), the Center for Human Immunology (led by Dr. Jordan Orange), and the NIH UDN Model Organism Screening Center and Knockout Mouse Phenotyping programs. For sustainability, BCM will 1) establish and financially support a Center for Undiagnosed Diseases, 2) leverage a newly developed DMHG virtual platform for medical genetics care delivery platform (Consultagene.org) to increase efficiency, decrease cost, and expand access for patient and provider engagement, 3) translate research tools to the clinical diagnostic arena, i.e., Baylor Genetics laboratory, 4) complete ongoing health economic studies to improve payor coverage for these tools, and 5) widely disseminate patient variants to stimulate collaboration with basic scientists for functional studies.